Healthcare-acquired infections (HAIs) are a major source of patient suffering and societal cost. Despite improved use of the most essential HAI control measure, hand hygiene by healthcare workers, adherence still lags and additional measures are needed. Three groups of interventions, comprising 6 studies, are proposed. First, multi-drug resistant organisms (MDROs) - methicillin-resistant Staphylococcus aureus (MRSA) and carbapenem-resistant gram-negative bacilli - and Clostridium difficile-associated infections (CDIs) are increasing causes of HAIs. MDROs often ping-pong between hospitals and long-term care;this highlights the importance of a regional, rather than the traditional institution-based, approach to control. The Chicago Prevention and Intervention Epicenter proposes T0/1/2/3 regional interventions in acute and long-term care facilities that will include enhanced surveillance and communication and patient cleansing with chlorhexidine to decrease MDRO risk in Chicago. Successful projects can inform MDRO control in other geographic areas. CDIs result in part from the effect of antibiotics on intestinal microbes. Probiotics, mixtures of natural gut- stabilizing bacteria, given to patients receiving antibiotic therapy have the potential to reduce risk of CDI. A T0/1/2 demonstration project of a novel probiotic that has shown promise for preventing CDIs is proposed. Second, device-related infections are addressed. Catheter-related bloodstream infections (CLABSIs) have declined due to wide application of interventions recommended in 2002 by CDC. Now, it may be possible to eliminate CLABSIs by controlling the major remaining infection source-extrinsic contamination of catheter hubs and fluid pathways. A T0/1/2 ICU and lab study of aggressive asepsis of catheter hubs is proposed. Catheter-associated urinary tract infection (CAUTI), although of lower morbidity, is a major MDRO reservoir and source of spread from hospitals into long-term care. A CAUTI technical innovation that has many early adopters despite absence of well-demonstrated efficacy is the handheld bladder scanner. These devices are expensive but provide the opportunity to determine bladder volume non-invasively. A T0/2 prospective controlled trial of bladder scanners for infection control is proposed. Third, we are facing MDROs with no new drugs. A T1/2 intervention to provide more rational antimicrobial use in ICUs, hot spots of resistance, is proposed. Educational activities that have been successful in other venues will be compared with the value of a biologic marker of bacterial infection - procalcitonin - for directing antimicrobial therapy. The impact on ICU infection and prescribing characteristics of doctors will be assessed. To further assess the interventions, costs of averted outcomes and of the interventions will be compared. OPRIONAL OBEJCTIVE SCORE: 2